Automatic Ultrasound Titration of Continuous Positive Airway Pressure (CPAP) Treatment for Sleep Apnea

ABSTRACT

Techniques for automated titration of CPAP device for a subject include receiving multiple ultrasound images representing a cross section of an airway in a neck of the subject at corresponding different times. Multiple different positive pressure values imposed by a device on the airway of the subject are also received at each of the corresponding times. For each of the ultrasound images, a mask of pixels associated with an air-tissue interface is automatically formed, and a value of a statistic of pixels within the mask is automatically determined. A titration pressure for a continuous positive airway pressure (CPAP) device is automatically determined based on the positive pressures and the value of the statistic for each of the ultrasound images. Output data that indicates the titration pressure for the CPAP device is presented on a display device, such as by operating the CPAP device itself at the titration pressure.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of Provisional Appln. 62/291,937, filedFeb. 5, 2016, the entire contents of which are hereby incorporated byreference as if fully set forth herein, under 35 U.S.C. § 119(e).

BACKGROUND

Obstructive sleep apnea (OSA) syndrome occurs with an estimatedprevalence of 2-9% in adult American population with an increasingincidence (Strollo et al. 1996; Shamsuzzaman et al. 2003). OSA has beenrecognized as a major cause of morbidity in recent years. The conditionis firmly seated within a spectrum of sleep-related breathing disorders(Flemons 2002), including snoring, upper airway resistance syndrome andobesity-hypoventilation syndrome. Left untreated, OSA can manifest inconditions with significant detriment to quality of life: daytimesleepiness (Johns 1993) and cognitive impairment (Findley et al. 1986).More significantly untreated OSA leads to increased morbidity andmortality from systemic and pulmonary hypertension (Marin et al. 2005),myocardial infarction (Hung et al. 1993), cardiac arrhythmias(Guilleminault et al. 1983), stroke and an increased risk of motorvehicle accidents (Teran-Santos et al. 1999). Given these implications,accurate and early diagnosis of OSA can potentially benefit earlyinterventions to halt initiation and progression of cardiovasculardiseases. However, due to the lack of consensus regarding specificdiagnostic tools and criteria, most of the subjects with OSA remainuntreated and the management of complications adds to the burden ofhealthcare costs.

Obstructive events occur when tissue in the upper airway collapsesduring sleep. This occurs during the negative pressure environment ofinspiration. The exact sites of collapse vary in each person dependingon their anatomy and to date there is no acceptable mechanism to predictor identify site of obstruction.

Treatment for sleep apnea events include continuous positive airwaypressure (CPAP) provided by a CPAP device. The process to determine thepositive pressure to keep an airway open is called CPAP titration. ACPAP titration study will typically follow an in lab diagnostic studyfor sleep apnea. The titration study itself is done in a lab and is forthe purposes of calibrating a CPAP machine to ensure CPAP therapy issuccessful at keeping the airway open and preventing a sleep apneaevent.

SUMMARY

Techniques are provided for the automatic collection of ultrasoundimaging data for titration of a CPAP device. In some embodiments thetechniques automate the determination of airway patency (openness) andcan be used for localization of an obstruction contributing toobstructive sleep apnea. Ultrasound is defined as pressure waves in amedium at frequencies higher than those detectable by normal humanauditory systems, and includes frequencies from about 20 kilohertz (kHz,1 kHz=10³ Hertz, 1 Hertz, Hz, is one cycle per second) up to aboutseveral gigahertz (GHz, 1 GHz=10⁹ Hertz). For use in non-invasiveimaging of human tissues to practical depths of tens of centimeters (cm,1 cm=10⁻² meters) ultrasound frequencies in the range from about 2 to100 megahertz (MHz, 1 MHz=10⁶ Hertz) are used. To avoid heating anddestructive effects, the power area density of such ultrasound waves isless than about 1 watt per square centimeter (Wcm⁻²).

In a first set of embodiments, a method includes automatically receivingmultiple ultrasound images representing a cross section of an airway ina neck of a subject obtained by an ultrasound transducer array directedtoward the subject at a corresponding plurality of different times; and,automatically receiving multiple different positive pressure valuesimposed by a device on the airway of the subject the correspondingmultiple different times. For each of the ultrasound images, the methodalso includes automatically forming a mask of pixels associated with anair-tissue interface; and, automatically determining a value of astatistic of pixels within the mask. The method still further includesautomatically determining a titration pressure for a continuous positiveairway pressure (CPAP) device based on the positive pressures and thevalue of the statistic for each of the ultrasound images. Even further,the method includes presenting on a display device output data thatindicates the titration pressure for the CPAP device.

In some embodiments of the first set, determining the titration pressureincludes determining the titration pressure based on one or more of thedifferent positive pressures which occur at one or of the correspondingdifferent times when the value of the statistic of pixels within themask is above a threshold value.

In some embodiments of the first set, presenting on a display deviceoutput data that indicates the titration pressure for the CPAP deviceincludes operating the CPAP device at the titration pressure.

In a second set of embodiments, a method includes automaticallyreceiving first multiple ultrasound images representing a cross sectionsof an airway in a neck of a subject obtained by an ultrasound transducerarray directed toward the subject at corresponding multiple differenttimes. The method also includes determining a region of interestcomprising a subset of pixels of each image of the first plurality ofultrasound images, wherein each region of interest encompasses an airwayof the subject. The method further includes, for each of the multipleultrasound images, automatically forming a mask of pixels associatedwith an air-tissue interface based on both a morphological opening and amorphological closing with a structural element in the region ofinterest if the mask includes at least a minimum number of pixels. Themethod still further includes, for each of the multiple images,automatically determining a value of a statistic of pixels within themask. The method yet further incudes presenting on a display deviceoutput data that indicates a degree of airway patency proportional tothe value of the statistic at each of the corresponding multipledifferent times.

In other sets of embodiments, a system or a non-transitorycomputer-readable medium is configured to perform one or more steps ofat least one of the above methods.

Still other aspects, features, and advantages of the invention arereadily apparent from the following detailed description, simply byillustrating a number of particular embodiments and implementations,including the best mode contemplated for carrying out the invention. Theinvention is also capable of other and different embodiments, and itsseveral details can be modified in various obvious respects, all withoutdeparting from the spirit and scope of the invention. Accordingly, thedrawings and description are to be regarded as illustrative in nature,and not as restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is illustrated by way of example, and not by wayof limitation, in the figures of the accompanying drawings, in whichlike reference numerals refer to similar elements and in which:

FIG. 1A and FIG. 1B are block diagrams that illustrate example open andobstructed airways, respectively, in a subject;

FIG. 2 is a block diagram that illustrates an example system forautomatic ultrasound imaging of a subject for determination of locationof an obstruction that could contribute to obstructive sleep apnea (OSA)or for automatic CPAP titration, or both, according to an embodiment;

FIG. 3 is a block diagram that illustrates an example rotating 1D arrayof ultrasound transducers used to acquire multiple 2D ultrasound images,as used according to some embodiments;

FIG. 4 is a block diagram that illustrates an example curved twodimensional array that follows a curvature of an attachment structurewhen the attachment structure is removably fitted around a neck of thesubject, according to some embodiments;

FIG. 5A through FIG. 5C are images from an endoscope and two slices ofultrasound returns, respectively, which illustrate example obstructedairway, according to an embodiment;

FIG. 5D through FIG. 5F are images from an endoscope and two slices ofultrasound returns, respectively, which illustrate example open airway,according to an embodiment;

FIG. 6A through FIG. 6M are images that illustrate automated processingsteps applied to image of FIG. 5F in order to find in an ultrasoundimage pixels associated with an air tissue interface that can be usedfor automated quantification of patency and possibly detection ofobstructions or automated CPAP titration, or some combination, accordingto various embodiments;

FIG. 7A through FIG. 7D are block diagrams that illustrate example shapefunctions that can be used in one or more steps illustrated in FIG. 6Athrough FIG. 6M, according to various embodiments;

FIG. 8A and FIG. 8B are block diagrams that illustrate example responseof an airway to an increase in CPAP pressure, according to variousembodiments;

FIG. 9 is a block diagram that illustrates a feedback loop for in anapparatus arranged to perform automated CPAP titration, according to anembodiment;

FIG. 10 is a graph that illustrates an example relation betweenautomatically determined pixel intensity at a tissue airway interfaceand CPAP pressure, according to an embodiment;

FIG. 11 is a graph that illustrates an example relation betweenautomatically determined pixel intensity at a tissue airway interfaceand automatic change in CPAP titration pressure, according to anembodiment;

FIG. 12 is a flowchart that illustrates an example method to treat asubject based on automatically determined pixel intensity at a tissueairway interface, according to an embodiment;

FIG. 13 is a flowchart that illustrates an example method to perform astep of FIG. 12 to determine CPAP titration pressure, according to anembodiment;

FIG. 14 is a block diagram that illustrates a computer system upon whichan embodiment of the invention may be implemented; and

FIG. 15 illustrates a chip set upon which an embodiment of the inventionmay be implemented.

DETAILED DESCRIPTION

A method and apparatus are described for the automatic titration of aCPAP device. In some embodiments the techniques automate thelocalization of an obstruction contributing to obstructive sleep apnea.In the following description, for the purposes of explanation, numerousspecific details are set forth in order to provide a thoroughunderstanding of the present invention. It will be apparent, however, toone skilled in the art that the present invention may be practicedwithout these specific details. In other instances, well-knownstructures and devices are shown in block diagram form in order to avoidunnecessarily obscuring the present invention.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope are approximations, the numerical values set forth inspecific non-limiting examples are reported as precisely as possible.Any numerical value, however, inherently contains certain errorsnecessarily resulting from the standard deviation found in theirrespective testing measurements at the time of this writing.Furthermore, unless otherwise clear from the context, a numerical valuepresented herein has an implied precision given by the least significantdigit. Thus a value 1.1 implies a value from 1.05 to 1.15. The term“about” is used to indicate a broader range centered on the given value,and unless otherwise clear from the context implies a broader rangaround the least significant digit, such as “about 1.1” implies a rangefrom 1.0 to 1.2. If the least significant digit is unclear, then theterm “about” implies a factor of two, e.g., “about X” implies a value inthe range from 0.5× to 2×, for example, about 100 implies a value in arange from 50 to 200. Moreover, all ranges disclosed herein are to beunderstood to encompass any and all sub-ranges subsumed therein. Forexample, a range of “less than 10” can include any and all sub-rangesbetween (and including) the minimum value of zero and the maximum valueof 10, that is, any and all sub-ranges having a minimum value of equalto or greater than zero and a maximum value of equal to or less than 10,e.g., 1 to 4.

Some embodiments of the invention are described below in the context ofultrasound transducers used in sequence without beamforming to detectreflected energy as a function of time from an airway in a subject.However, the invention is not limited to this context. In otherembodiments ultrasound transducers are arrayed to detect transmitted,refracted and scattered energy in addition to or instead of reflectedenergy from the airway or other tissue structures of the subject, withor without beamforming and with or without computed tomography.

1. Review

Historically, diagnosis of OSA has been achieved through historyobtained from the subject and the sleep partner. To increase thesensitivity and specificity of diagnosis, numerous studies haveadvocated the addition of polysomnographic testing (Riley et al. 1993)that includes a battery of measures including blood oxygenation levelsduring the apneic episodes, physiological measures such as heart rate,respiratory rate and electroencephalography (EEG). Polysomnography in acertified sleep lab is the gold standard for diagnosis of OSA in currentmedical care. Other joint task force recommendations (Veasey 2006;Collop 2007) identified a cohort of subjects who could be candidates forportable monitoring (PM) through application of probes and sensors thatspecifically measure physiological parameters during the episodes ofapnea. A large volume of literature has thus evolved, concentrating onthe following parameters (Collop 2007): 1. Oximetry; 2. Respiratorymonitoring including a) Effort, b) Airflow, c) Snoring, d) End-tidalCO2, e) Esophageal pressure; 3. Cardiac monitoring, not limited to: a)Heart rate or heart rate variability, b) Arterial tonometry; 4. Measuresof sleep-wake activity such as a) Electroencephalography, b) Actigraphy;5. Body position; and 6. Miscellaneous others.

While monitoring technology for these measurements has largely been inplace especially during polysomnography (PSG) testing, traditionallycalled a sleep study, these pave the way only for diagnosis and arespecifically deficient for accurate localization of obstructivephenomena. The importance of localization (site of obstruction imaging)is in treatment, wherein an area of obstruction could be surgicallyameliorated; or monitored to determine a minimum pressure for continuouspositive airway pressure (CPAP), a process called CPAP titration. Thus,diagnosis alone is not sufficient for reducing the progression of thesyndrome; does not specifically address the site(s) of obstruction; and,thus does not specifically assist titrating continuous positive airwaypressure (CPAP) that works by pneumatically stenting the airway.Furthermore, a technique to monitor and identify the site of obstructioncould be a significant milestone in formulating long-lasting treatmentstrategies for an individual diagnosed with OSA.

The simplest method for assessment of airway geometry involves use ofthe lateral skull and neck radiographs for cephalometric calculations. Asummary of these radiographic findings (Deberry-Borowiecky et al. 1988)in these subjects include (a) enlargement of the tongue and soft palate.(b) inferior displacement of the hyoid bone (c) normal size and positionof the mandible, yet changes in the relative positions of landmarks onthe mandible itself (d) backward displacement of the maxilla andelongation of the hard palate and (e) normal nasopharynx, but reductionin the oropharyngeal and hypopharyngeal airway diameters. Incombination, these findings illustrate the presence of multi-segmentalchanges within the aerodigestive tract that may be targeted withsurgical procedures (Guilleminault et al. 1984; Riley et al. 1985).However, the major disadvantage with these radiographic assessmentsconcerns simultaneity, i.e. obstructive phenomena may occur at multiplelevels but the lack of resolution of x-ray findings preventscategorization of obstruction into major and minor phenomena, hence theylose their relevance for accuracy in localization for targetedtreatment. Lateral cephalogram radiography also fails to elucidate theimportance of soft tissue in the etiology of apnea. A modified techniquefor obtaining radiographs, i.e. fluoroscopy, wherein live imaging of theairway could be obtained using continuous x-ray exposure has highersensitivity and specificity (Pepin et al. 1992). However,somnofluoroscopy is unsuitable for introduction as a screening tool dueto exposure to ionizing radiation.

An alternate technique that has been frequently used in literatureincludes the use of high-resolution CT scans (Bhattacharyya et al. 2000;Rodenstein et al. 1990). Here, the resolution is markedly improved withcurrent technology that permits extremely thin slice acquisitions, andmay be combined with a trigger-activated circuitry using pulse oximetry,obtaining scans that may be acquired specifically during the time ofobstruction. As promising as it sounds, there are several problemsassociated with deployment, namely exposure of subjects to high levelsof ionizing radiation, loss of natural sleep patterns during acquisitionwithin the scanner bay, and costs. Similar problems exist for use of MRIscanners; even as they increase the resolution of soft tissue imaging(Schwab et al. 2003; Shelton et al. 1993). MRI scanners are noisy, withpotential to disrupt sleep; and the time taken for acquisition of imagesmay be prohibitive for large-scale screening; with additional problemsassociated with motion-artifacts.

One of the earliest studies for localization of OSA obstruction focusedon simultaneous monitoring of pressures in the posterior nasopharynx,oropharynx, hypopharynx, and esophagus during overnight polysomnography(Shepard et al. 1990). From the profile of pressures recorded in theupper airway and esophagus, the regions over which the airway collapsesduring apneic episodes could be determined. While this study yielded thedegree of relationship between the pressures and PSG-derived indices,this mandated insertion of monitoring probes invasively within the upperaerodigestive tract and the limitation of the number of subsitesindicated that the overall resolution was poor. Others (Chaban et al.1988) that focused on insertion of catheter-based transducers such asthe Millar device also reported benefits in measurement. Conceivableissues with long-term measurements include problems with loss of naturalsleep architecture owing to the presence of a device in the upperairway, and safety issues concerning migration and potential for thedevice itself to cause obstruction. Furthermore, animal models oftenconclude that there is poor relationship (Hudgel 1986) between pressuregradients measured using deployable transducers and the surgicaloutcomes following procedures such as uvulopalatopharyngoplasty (UPPP).

In assessments of subjects prior to undergoing sleep surgery, a flexiblefiberoptic endoscopic examination of the upper airway has beenrecommended (Croft et al. 1991) with some confidence owing to therelative ease of this procedure. However, this technique cannot identifysubjects who have multisegmental anatomic obstruction (Morrison et al.1993), and those individuals cannot be accurately tested because themeasurements are done in the setting of a clinic in an awake state.

Ultrasound technology has been refined and modified for use in areassuch as medical imaging (McNay et al. 1999), non-destructive testing(Silk 1984), industrial processing applications (Ruecroft et al. 2005),cleaning (Muthukumaran et al. 2004), and range finding (Kuratli et al.2000). Devices used for biomedical applications have been repeatedlyappraised and found to be safe (Hoskins et al. 2010) and suitable foruse in a variety of settings, such as obstetric (Romero 2003) and fetal(Crane et al. 1994) diagnostic techniques, cardiac and vascularapplications including devices such as catheters and probes (Gardin etal. 2006; Hamers et al. 2001).

Ultrasonic devices for use in diagnosis of obstructive sleep apnea havenot been thoroughly evaluated thus far; an extensive MEDLINE search forterms “ultrasound” and “obstructive sleep apnea” produced just fourrelevant results. Two of these articles specifically evaluatedultrasound for prediction of difficult laryngoscopy in obese subjects(Ezri et al. 2003) and for identification of anatomic landmarks prior toprocedures such as tracheostomy and cricothyroidotomy (Kajekar et al.2010). The third, a dissertation (Girard 2003), evaluated a standardultrasound system to obtain images of the area of the pharynx involvedin OSA and utilized image processing algorithms for detection ofobstruction. This work also showed that the extracted active contours ofthe airway accurately detected its state (open or obstructed) in twodimensional axial images of the pharynx. In addition, the author showedthat a motion detection algorithm could quantify tongue base movements.Lastly, yet another manuscript (Siegel et al. 2000) evaluated therelationship between ultrasound-derived images and clinicalpolysomnographic indices, and found good correlation between multiplevariables.

2. Overview

Here is described a method and system that enables one to localize asite of obstruction in subjects with OSA using ultrasound technology andto monitor that site during CPAP titration to determine therapeuticpositive pressure for CPAP treatment. To illustrate how the devicefunctions, it is useful to show an example of an airway obstruction inthe context of the airway anatomy. FIG. 1A and FIG.1B are block diagramsthat illustrate example open and obstructed airways, respectively, in asubject. The anatomical features of the subject include a soft palate120, tongue 130 and pharynx 140. An airway is a lumen that includesnasal sinuses inside the nose, a retropalatal portion 122 behind thesoft palate 120, a retrolingual portion 132 behind the tongue and ahypopharyngeal portion 142 in front of the pharynx. FIG. 1A depictsnormal airflow through the nose (nasal air flow 110 a) past the palate120 and tongue 130 and pharynx resulting in normal net air flow 118 a.In particular the airway is open in portion labeled open airway 191.FIG. 1B depicts an obstructed airway 192 in the retrolingual portion ofthe airway corresponding to open airway 191 in FIG. 1A. This results inobstructed net airflow 118 b that leads to mouth breathing indicated bylingual air flow 112, or snoring, or insufficient oxygenation of thesubject's blood, or some combination, or worse, leads to essentiallyzero net flow and risk of death if the subject does not awake in time.

2.1 Structural Overview

In various embodiments, a system is configured to automatically scan theairway during an obstructive sleep apnea (OSA) event using ultrasound,to provide ultrasound image data that can be used to localize anobstruction, either manually or, in some embodiments, automatically, andto automatically perform CPAP titration based on the localizedobstruction, whether the obstruction is localized automatically ormanually. FIG. 2 is a block diagram that illustrates an example system200 for automatic ultrasound imaging of a subject for determination oflocation of an obstruction that could contribute to obstructive sleepapnea (OSA) or for automatic CPAP titration, or both, according to anembodiment. As used herein, a subject can be any organism with lungs,including animals, mammals and humans, alive or dead. Although a subject290 is depicted for purposes of illustration, subject 290 is not part ofsystem 200.

The system 200 includes an ultrasound imaging device 210, an apnea eventsensing device 220, a CPAP system 260 and a computing system 240, indata communication with each other through one or more datacommunication channels 230.

The illustrated ultrasound imaging device 210 includes an ultrasoundtransducer array 212, attached to the subject by an attachment structure216 such as a strap or belt or collar, and a imaging command module 214.A variety of suitable imaging devices for various embodiments aredescribed in U.S. Patent Application Publication No. US2015/0209001(hereinafter, Wolf et al., 2015), the entire contents of which arehereby incorporated by reference as if fully set forth herein. Ifbiplane (rotary sagittal plane) ultrasound transducers are of interest,an E14CL4b endocavity biplane (Analogic Corp, Peabody, Mass.); 3DARTtype 8808 (Brüel & Kjær, Herlev, Denmark) or HD15 BP10-5EC BiplaneCurved Array (Philips Healthcare, Andover, Mass.) can be used. Analternate arrangement uses simultaneous biplane scanning with onescanner apiece for each plane, e.g., coronal and sagittal, andsubsequent reconstruction by combining sequences using morphologicalreconstruction. An additional alternate arrangement is configured bycombining more than one transducer in each plane. If single-plane, thenuseful transducers are a C60e transducer (5-2 MHz, Sonosite, Bothell,Wash.), a L12-5 transducer (12-5 MHz, Philips Healthcare, Andover,Mass.), or a L4-12t-RS transducer (12-4 MHz, Wauwatosa, Wis.).

The ultrasound transducer array 212 is a set of two or more ultrasoundtransducers arranged in one or two dimensions configured to operatetogether to introduce or detect ultrasound waves. An ultrasoundtransducer is a component that either produces an ultrasound wave inresponse to an electrical or optical signal (also called an ultrasoundtransmitter), or produces an electrical or optical signal in response toan impinging ultrasound wave (also called an ultrasound receiver ordetector), or both (also called an ultrasound transceiver). In variousembodiments, ultrasound transducers are arrayed to detect transmitted,reflected, refracted or scattered energy from the airway or other tissuestructures of the subject, with or without beamforming, and with orwithout computed tomography. Many ultrasound transducers appropriate forprobing human tissues are known in the art and any may be used invarious embodiments. Example ultrasound transducers are described below.The ultrasound transducer array 212 is configured to produce data formultiple ultrasound images representing corresponding multiple crosssections of an airway of the subject 290 at multiple different times, asdescribed in more detail below.

The imaging command module 214 is a component that powers and activatesthe transducer array and transmits data representing the receivedsignals that are used to construct an image. In some embodiments, thecommand module also constructs the image data based on the receivedsignals. Many ultrasound probes are commercially available with acommand module and transducer array as an integrated unit. Examples ofsuch integrated ultrasound probes include: icte and c60e from SONOSITE™of Bothell, Wash.; 8820e from ANALOGIC™ Corporation, Peabody, Mass.;10C-D, 10C-SC, 3S-SC, RAB series from GE HEALTHCARE™, Little Chalfont,Buckinghamshire, United Kingdom; EUP-C715, C514, C516, C511, C524 andC532 (convex probes) from HITACHI ALOKA™ Medical America, Wallingford,Conn.; SP2730, CA1123, LA533, LA523 from ESAOTE™ North America, Inc.Indianapolis, Ind.

The CPAP system 260 includes an electrically controlled pump 262connected by air hose 263 to face mask 264 configured to fit over thenose and mouth of the subject 290. In some embodiments, the system 260includes one or more sensors configured to detect the air pressure andzero or more other properties, such as temperature, of the volume of airinside the face mask and mouth and nose of the subject 290. Signalsrepresenting commands for the pump, such as a pumping rate or targetpressure are supplied by the processing system 242 through one or morecommunication channels 230. In some embodiments, data indicating themost recent command or a series of commands is stored locally on thepump. Signals representing the detected pressure and zero or more otherproperties are transmitted through one or more of the communicationchannels 230 to the pump 262 or processing system 242, or somecombination. Example CPAP systems include Transcend Auto MINICPAP™Machine (Somnetics, New Brighton, Minn.); AIRSENSE™ 10 AutoSet (ResMed,San Diego, Calif.); PR System One REMStar 60 Series (PhilipsRespironics, Murrysville, Pa.); XT Fit CPAP Machine (Apex Medical, NewTaipei City, Taiwan); Icon Auto CPAP (Fisher & Paykel, Auckland, NZ).

The computer system 240 is one or more devices, such as a computersystem 2000 described in more detail below with reference to FIG. 20, ora chip set, such as chip set 2100 described in more detail below withreference to FIG. 21 and used for example in a portable or mobile devicesuch as a cell phone or tablet. The computer system is configured tocontrol the operation of the ultrasound imaging device 210, and toproduce, present or store all or part of the ultrasound image data, orsome combination. Many commercially available ultrasound probes areavailable with terminal equipment that performs some or all of thefunctions of the computing system 240. Examples of such ultrasoundimaging terminals include point of care stations for one or more of theabove probes and MyLab Twice, MyLab Seven, MyLab Gold from ESAOTE™ NorthAmerica, Inc. Indianapolis, Ind.; and, Voluson E10, E8 and E6, Vivid E9,S6, q, S5 LOGIQ e Ultrasound BT 12 from GE HEALTHCARE™, Little Chalfont,Buckinghamshire, United Kingdom.

The computing system 240 is also configured to control the operation ofthe CPAP system. Example CPAP systems that can be controlled byexternally provided digital or analog commands include iVent 201 fromVersaMed, Pearl River, N.Y. and Stellar 150 from ResMed, San Diego,Calif.

According to the illustrated embodiment, the computing system 240includes at least a processing system 242 and storage device 245. Theprocessing system 242 includes hardware and software configured toperform the steps of a novel controller/analysis module 250, asdescribed in more detail below with reference to flow charts in FIG. 12and FIG. 13. At least some image data that indicates location of anobstruction during an obstructive sleep apnea (OSA) event is stored asultrasound image data 252 on storage device 245, which is one form ofcomputer-readable memory, as described in more detail below withreference to FIG. 14 and FIG. 15.

Rather than have the ultrasound imaging device 210 and computing system240 perform the computationally, algorithmically and power demandingtask of constantly imaging the tissues and airways of the subject todetermine the timing of an OSA event, in some embodiments, The systemdetermines the timing of an OSA event based on a separate apnea eventsensing device 220. The device 220 includes an apneas sensor set 222 ofone or more sensors that collect measurements that are sensitive to theoccurrence of an OSA event, such as interruption of normal chestmovement rhythms, a drop in blood oxygen saturation levels, or theinterruption of normal acoustic rhythms such as the sounds of breathingor snoring. Sensors typically used for such purposes include microphonesto detect the audible sounds made by the subject, blood oxygensaturation sensors such as a pulse oximeter attached to a subject'sfinger, and one or more accelerometers attached to a subject's chest.The absence of airflow (sensor output) during sleep (EEG) while thechest is moving with resultant decreased saturation (desat) is how asleep lab would diagnose and OSA event. Example sensors include Airflowsensors, Pulse Oximeter, chest movement sensors, and EEG (to detectsleep), such as SOMNOSTAR™ v4 from VIASYS™ Inc of Conshohocken, Pa.;and, e-series and SOMTEPS™ from COMPUMEDICS™ , Victoria, Australia. Suchsensors are simpler, more rapid or more cost effective than theultrasound imaging device 210, or offer some combination of theseadvantages. In some embodiments, it is advantageous to use at least twosuch sensors, of the same or different types or some combination, toprovide reliability and redundancy as a safeguard against failure of asingle sensor.

In the illustrated embodiment, the apnea event sensing device 220includes a sensor set command module 224 to power or control the sensorsin the sensor set 222, ensure the sensors are functioning properly, orsend an alarm when the sensor data indicates an OSA event, or somecombination. In embodiments involving CPAP titration, the titrationprocess itself may prevent the occurrence of a sleep apnea event; and,in some such CPAP titration only embodiments, the apnea event sensingdevice 220 is omitted.

The data communication channels 230 are wired or wireless channels(including BLUETOOTH and WiFi) in direct or networked communicationwithin, between or among two or more of the ultrasound imaging device210, CPAP system 260, apnea event sensing device 220 and computingsystem 240. One or more of the devices 210, 220, 240, 260 is configuredto establish communications within or among the devices, for exampleusing standard networking protocols.

The system 200 is configured such that, when an OSA event is detectedbased on data from the advantageous sensors of the apnea sensor set 222,a signal is sent to the ultrasound transducer array 212 to collectimaging data for forming images of the airway of the subject at multiplecross-sections of the airway, from the retropalatal region down past thehypopharyngeal region. Thus, data is collected that can indicate thelocation of an obstruction. In some embodiments, a human analyst reviewsthe images to determine the occurrence of any obstruction. In someembodiments, the system automatically identifies one or more of theimages, or regions within the images, or some combination, with featureslikely to indicate the location of an obstruction.

After the obstruction location is determined, either automatically ormanually, that location is monitored using multiple subsequentultrasound images collected at corresponding multiple different timeswhile increasing pressures are exerted by the CPAP system in a CPAPtitration process. That process automatically terminates when thepressure applied is sufficient to maintain or re-open an open airwaywithout being unduly uncomfortable to the subject. For example, in someembodiments, the pressure increase is mapped to the number of sleepapnea events, and the titration pressure is reached when the count dropsbelow a certain level, e.g., 1 event per night. In other embodiments,the pressure is not applied until a sleep apnea event is detected, thena slowly increasing pressure is applied to re-open the airway. Eachpressure increment is coordinated with an ultrasound image through theobstruction location. The pressure that re-opens the airway isconsidered a potential CPAP pressure. Because the pressure to re-open anairway might be greater than the pressure sufficient to prevent closingof the airway, in some embodiments, the potential CPAP pressure isreduced slightly and maintained to obtain a count of sleep apnea eventsat the slightly reduce pressure. The process is repeated until apressure is found that separates an unacceptably high count of sleepapnea events (e.g., more than X event per 8 hours of sleep, where Xvaries from about 1 to bout 5) from an acceptable count of sleep apneaevents (e.g., X events or fewer than X events per eight hours of sleep).In some embodiments, a strength of the air-tissue interface is know tobe associated with unobstructed sleep, and the pressure is increaseduntil that strength is achieved without waiting for a sleep apnea eventto occur which is expected to be rare.

Although processes, equipment, and data structures are depicted in FIG.2 as integral blocks in a particular arrangement for purposes ofillustration, in other embodiments one or more components or processesor data structures, or portions thereof, are arranged in a differentmanner, on the same or different equipment, in one or more databases, orare omitted, or one or more different components or processes or datastructures are included on the same or different equipment. For example,processing done by the imaging command module 214 or the sensor setcommand module 224, or both, may be performed in whole or in part by thecontroller/analysis module 250 in the computer system 240. Likewise,some or all functions performed by the controller/analysis module may beperformed by the imaging command module 214 or sensor set command module224, or some combination.

Thus, the system 200 includes an ultrasound transducer array 212configured to be disposed adjacent to a neck of a subject, a continuouspositive airway pressure (CPAP) device 260, at least one processor 242;and at least one computer-readable medium 245. The computer-readablemedium include one or more sequences of instructions, such that the atleast one medium and the one or more sequences of instructions areconfigured to, with the at least one processor, cause the system toperform at least the following steps. The system automatically receivesmultiple ultrasound images representing a cross section of an airway ina neck of the subject obtained by the ultrasound transducer arraydirected toward the subject at corresponding multiple different times.The system automatically receives data indicating multiple differentpositive pressure values imposed by the CPAP device on the airway of thesubject at the corresponding multiple different times. For each of themultiple ultrasound images, the system automatically forms a mask ofpixels associated with an air-tissue interface, and automaticallydetermines a value of a statistic of pixels within the mask. The systemalso automatically determines a titration pressure for the CPAP devicebased on the multiple positive pressures and the value of the statisticfor each of the multiple ultrasound images. In addition, the systemoperates the CPAP device at the titration pressure.

FIG. 3 is a block diagram that illustrates an example rotating 1D array322 of ultrasound transducers used to acquire multiple 2D ultrasoundimages, as used according to some embodiments. The array 322 is depictedin side view looking along the axis of rotation so that the angularrotation is in direction 323. The rotating 1D array 322 is housed in anultrasound imaging device 320, which can be held in place to simulate adevice strapped to the throat of the subject 390. Although depicted forpurposes of illustration, the subject 390 is not part of the device 320.

In one orientation, the 1D array 322 produces a 2D image along a crosssection perpendicular to the view of FIG. 3 along a top side 331 oftrapezoidal region 330. In a different orientation, the 1D array 322produces a 2D image along a cross section perpendicular to the view ofFIG. 3 along a bottom side 332 of trapezoidal region 330. In betweenthese two images, multiple 2D images are produced along interveningcross sections. Note that the cross sections are not parallel in thisembodiment, but yet sample the airway from the retropalatal domain 122,through the retrolingual domain 132 and the hypopharyngeal domain 142 tothe mid-tracheal domain 352.

To study the automated identification of an ROI encompassing anobstruction, the ultrasound imaging device 320 was used in anexperimental embodiment in which the subject was a cadaver. The cadaverwas surgically altered to allow tissue collapse to be induced. Softtissue collapse was induced by application of sustained negativepressure (−5 cm of water) via a reversed tracheostomy tube. Thisnegative pressure just exceeds the mean critical pharyngeal closingpressures in humans.

FIG. 4 is a block diagram that illustrates an example curved twodimensional array 410 that follows a curvature of an attachmentstructure 416 when the attachment structure is removably fitted around aneck of the subject, according to some embodiments. The individualultrasound transducers 412 are affixed to the removable attachmentstructure 416. Thus, FIG. 4 illustrates a circumferential scannerassembly 400 that holds the transducers. In some embodiments, theassembly 400 is held within an expandable, elasticated and tubularfabric (e.g. Dacron) with radial and linear reinforcements as attachmentstructure 416. These reinforcements prevent the proximal-to-distal andlateral migration of the assembly 400.

FIG. 5A through FIG. 5C are images from an endoscope and two slices ofultrasound returns, respectively, which illustrate example obstructedairway, according to an embodiment. FIG. 5D through FIG. 5F are imagesfrom an endoscope and two slices of ultrasound returns, respectively,which illustrate example open airway, according to an embodiment. Theairway in the cadaver model is nearly closed as depicted in FIG. 5A sothat the endoscope can not penetrate further to actually image theobstruction, while the airway is open much wider in FIG. 5D. Theultrasound images are bright where a strong acoustic reflection ismeasured and dark where there is little and black where there is none.The airway would be in the posterior 40%, indicated by the horizontalarrow 502 and vertical arrow 504, because in this experiment theacoustic source is at the throat as depicted in FIG. 3 at the bottom ofthe images. The posterior 40% of the ultrasound images show very lowsignal. Yet this is the area where an open airway would present anair-tissue interface and a strong reflection signal. The rectanglesindicate a small reflection attributed to a pocket of air in the crosssection and were placed manually. These small areas of bright pixels arecompatible with the significantly diminished air column observed anddepicted in FIG. 5A. In contrast, when the airway in the cadaver modelis open as depicted in FIG. 5D, the ultrasound images depicted in FIG.5E and FIG. 5F are bright where an open airway presents an air-tissueinterface and a strong reflection signal in the back third of the image.The bright areas attributed to the open airway are marked by a brightoutline that has been imposed manually on the image. As can be seen, thenumber of bright pixels is related to the degree of opening of theairway. A challenge is to detect the bright airway pixels automatically.

In various embodiments, ultrasound cross-sectional images of the airwayare automatically processed to determine the area of high reflectionattributable to the tissue-airway interface. In some of theseembodiments, the manual outlines are used to define manually-determinedmasks that establish the presence of an air-tissue interface. Thesecorrespond to wherein an air column is present. The mask is confined tothe top 40% of the neck (posterior in transducer orientation) as theair-tissue interface is always found in the same location. Spatialrestriction of the mask reduces contamination from artifacts.

FIG. 6A through FIG. 6M are images that illustrate automated processingsteps applied to the image of FIG. 5F in order to find in an ultrasoundimage pixels associated with an air tissue interface that can be usedfor automated quantification of patency and possibly detection ofobstructions or automated CPAP titration, or some combination, accordingto various embodiments.

The representative image of FIG. 5F with a prominent air-tissueinterface is first dilated using a diamond-shaped structuring elementthat is convolved with the original image, producing the image of FIG.6A, reduced in scsle to allow multiple such processed images to bepresented in the figures. The diamond shaped structural element isdepicted in FIG. 7A. In other embodiments, other shapes of dilationstructural elements are used. FIG. 7A through FIG. 7D are block diagramsthat illustrate example shape functions that can be used in one or moresteps illustrated in FIG. 6A through FIG. 6M, according to variousembodiments. A value of 1 is inside the element and a value of zero isoutside the element for a window of 7 pixels by 7 pixels containing thediamond structural element. During the dilation, the structural elementis centered on a pixel in the original image, and the original value atthat pixel is multiplied by the value of the structural element andplaced in the corresponding positon in the processed image relative tothe original pixel at the center of the structural element. Alternativeshapes are compared to the diamond values. The target shapes areoutlined by broken lines and represent the pixels of interest to beconvolved with a value of 1, and the pixels outside (neighborhood)represent other pixels convolved with a value of 0 (only the diamondvalues are actually shown for comparison). FIG. 7B shows a hexagonaloutline; FIG. 7C shows a circular outline; and, FIG. 7D shows arectangular outline. The size and shape of the structuring element maybe set manually, following inspection of the air-tissue interface in aninitial scan of the neck soft tissues. Other shapes and sizes may bedrawn in a custom fashion, should the target airway interface not beaccurately modeled by any of the above structural element shapes. Thediamond-shaped structuring element was chosen to approximate the contactsurface of a transducer (rectangle) making tangential contact with acylinder (approximating the shape of the neck). It is reasonable toexpect a rectangular structuring element would be advantageous for aninterface that is perpendicular to the ultrasound transducer, but inpractice the best structuring element shape is determined by experimentsand is expected to be based on the patient's anatomy.

The dilation results in enlargement of the boundaries of regions deemedto contain bright pixels within the foreground, as depicted in FIG. 6A.It is possible to change the sensitivity and specificity of detection byproviding an option to change the threshold for what is consideredbright, e.g. 150 grey level units. Foreground on the other hand couldinclude all non-zero values within the image. The converse occursfollowing erosion, which partially removes the interfaces of brightforeground pixels, as depicted in FIG. 6B for the same original imagepresented at the same scale. Morphological opening results inpreservation of foreground regions that have a similar shape to theoriginal structuring element, while eliminating all other regions offoreground pixels. The result of morphological opening is depicted inFIG. 6D for the same original image at the same scale. Closing resultsin preservation of the dark pixels (ascribed to a “background region”)that have a similar shape to the structuring element is shown in FIG.6C. Although any of these morphological operations may be used toreconstruct the air-tissue interface, the best results are obtained inthis instance with an eroded image (also called a “marker” image) thatis operated on by morphological opening utilizing the original image. Inthis reconstruction, the eroded image of FIG. 6B is repeatedly dilateduntil its contours fit the manual mask generated from the originalimage. This result is shown in FIG. 6E, at a larger scale.

Using the latter approach, the original image was first eroded followedby dilation (morphological opening) to produce FIG. 6F, presented at thesmaller scale, again, for convenience. Following this, the regionalmaxima were estimated. Regional maxima are connected edges of pixelswith a constant intensity value, and whose external boundary pixels arelower. The estimation method uses 8-connected neighborhoods in thisexample, but may be increased or decreased neighborhoods in otherembodiments to optimize detection.

In an alternative approach, the original image undergoes dilation firstand then erosion producing the image of FIG. 6G, presented at thesmaller scale. Regional maxima were also estimated in a similar fashion.

The regional maxima of FIG. 6E were also obtained and shown in FIG. 6H,again at the smaller scale. The image of FIG. 6I represents the effectof removing small objects, deemed to contain fewer than 20 pixels, fromthe image of FIG. 6H. The definition of small objects to be removed maybe increased or decreased as desired in various embodiments. FIG. 6Jpresents at the larger scale, the outlines of the regional maximadepicted in FIG. 6I. These outlines, when filled with the value 1 insideand the value 0 outside, serve as a mask that can be used to determinethe statistics of pixels in the air-tissue interface. The maximum valueinside these outlines (within the mask) on the original image producethe spots plotted in FIG. 6K over the original image. Mean pixelintensity was calculated within the marked regions in the posterior 40%and compared to manual estimations. In FIG. 6L, presented at the largerscale, the bright pixels of the mask of FIG. 6I within the box demarkingthe posterior 40% represent air-tissue interfaces corresponding to anair column and used to calculate area of the air-issue interfaces. Inother embodiments, other statistics of the bright pixels can be used,such as the average intensity in the original image within a mask formedby the bright areas of FIG. 6L in the posterior 40%, or median (50^(th)percentile) or the 75^(th) percentile or other percentile intensityvalue inside the mask among others.

For example, in some embodiments, the posterior 40% (alternatively, 50%)of each image is selected automatically for further processing. A medianfilter is applied automatically to remove the noise within the selectedportion of the image. A Gaussian curve is fit automatically over thedistribution of pixel intensities in the selected portion. The Gaussiancurve is automatically split into a predetermined number n of bins, withn predetermined to be in a range from about 3 to about 5. In someembodiments, the bin size is determined automatically to be one standarddeviation from the Gaussian curve fit step. The bins to the right of themedian are examined automatically to determine which bin boundary willserve as the bright interface (mask boundary). The result is illustratedin FIG. 6M, which is an example ultrasound image of the upper airway,axial section. One contour represents the far right bin (above 3standard deviations) of the Gaussian fitted to pixel intensities withinthe top half of the image. Note that the contour wraps around the edgesof the pixels having intensities in the selected bin. Other contoursrepresent other bin boundaries at 2 standard deviations and 1 standarddeviation, respectively, serving as the bright interface (mask boundary)in other embodiments.

FIG. 8A and FIG. 8B are block diagrams that illustrate example responseof an airway to an increase in CPAP pressure, according to variousembodiments. Major potential sites of upper airway obstruction arelabeled (tongue, palate and hypopharynx). A fitted mask attached to theCPAP machine is also shown. Insufflation pressures are derived by a CPAPcontrol unit. The imaging extent of the ultrasound transducer (5 MHzcenter frequency) is demonstrated by a greyed-out zone. In FIG. 8A theairway is obstructed by the posterior portion of the tongue in theretrolingual region. FIG. 8B shows upper airway obstruction relieved byadjustments in pneumatic pressure delivered by the CPAP machine. Thiseffect should be noticed in ultrasound cross sectional images thatilluminate the retrolingual region.

FIG. 9 is a block diagram that illustrates a feedback loop for in anapparatus arranged to perform automated CPAP titration, according to anembodiment. Application of pressure to the upper airway is by means of acomposite mask 901 fitted to the lower face, covering the mouth and thenose, with an attached relief valve 902 to protect againstover-inflation. A pneumatic pump (e.g., insufflator motor 903) drivesthe insufflation of the airway by delivery via the mask 901. Theinsufflation feedback is controlled using information from an attachedbarometric sensor 904. These components are all powered by an external,but isolated and grounded power supply 905. The master controlmechanisms are modules configured on one or more microprocessors (e.g.,906 and 907) that are in communication with the ultrasound scanner, suchas scan collar 908, which provides an estimate of airway obstructionusing one or more of the microprocessors 906 and 907 to perform imageprocessing as described above based on overall measurement ofairway-tissue interface pixel intensities. One or more microprocessors906 and 907, cycle the pressure used to insufflate the CPAP mask,forming one or more feedback loops 909 and 910.

This amount of pressure to apply calculated in the feedback loop isexplained graphically, with an inverse relationship between CPAP driverpressure (Pd, in cm of water, y-axis) and the normalized pixel intensity(x-axis) of the region of interest determined in an automated fashionusing the image processing protocol described above. FIG. 10 is a graphthat illustrates an example relation between automatically determinedpixel intensity at a tissue airway interface and CPAP pressure,according to an embodiment. The horizontal axis 1002 indicates meanpixel intensity in units of grey level. In other embodiments, thehorizontal axis is number of bright pixels in the mask of FIG. 6L. Thevertical axis 1004 indicates CPAP driver pressure (Pd) in units ofcentimeters of water. An example threshold of 150 grey level units isachieved at a re-opening pressure (that matches the closing pressure ofthe upper airway). Thus this pressure associated with 150 grey levelunits is the titrated pressure discovered. The CPAP is operated at thisinsufflation pressure to prevent barotrauma. This threshold can beadjusted according to subject comfort, e.g., reduced somewhat as long asthe bright pixel count or mean pixel intensity within the mask does notfall too far below the threshold levels. Some embodiments use a dial orother control to select a value in the range from about 100 to about 150grey level units for mean intensity and then use a second dial or othercontrol to select a number of standard deviations above that within themask, e.g. 1 to standard deviations in intervals of about 0.5 standard.

FIG. 11 is a graph that illustrates an example relation betweenautomatically determined pixel intensity at a tissue airway interfaceand automatic change in CPAP titration pressure, according to anembodiment. The horizontal axis 1102 indicates proportion change in meanpixel intensity and the vertical axis 1104 indicates CPAP pressure in cmH2O. Example functions 1111 and 1112 are shown for titrating CPAPpressures from fitting to measurements of the airway degree of opennessfrom the ultrasound images (called ultrasonographic estimation of airwaypatency), as measured by bright pixel count or mean pixel intensitywithin the mask. Functions marked 1111 and 1112 (linear and exponential)model the measured relationship between insufflation pressure using CPAP(y-axis) and the proportion change in mean pixel intensity (x-axis). Themean pixel intensity may be titrated to a desired ‘set-point’represented by zero on the horizontal axis 1102, according to subjectcomfort. Once this set point is reached, the CPAP pressure can bereduced. Other functions that may be biologically appropriate includethe Cantor function, characterized by linear non-monotonic growthobserved between pixel intensity and CPAP driver pressure, with acentral ramp pressure that may be held for a range of pixel intensities.The ramp function is a CPAP feature that auto-adjusts pressure until theramp maximum is reached, beyond which the pressure is held constant sothat airway is protected from over-inflation.

2.2 Method Overview

FIG. 12 is a flowchart that illustrates an example method to treat asubject based on automatically determined pixel intensity at a tissueairway interface, according to an embodiment. Although steps aredepicted in FIG. 12, and in subsequent flowchart FIG. 13, as integralsteps in a particular order for purposes of illustration, in otherembodiments, one or more steps, or portions thereof, are performed in adifferent order, or overlapping in time, in series or in parallel, orare omitted, or one or more additional steps are added, or the method ischanged in some combination of ways.

In step 1201, an ultrasound transducer array 212 is provided, such asarray 310 a, and is configured to produce first data (e.g., reflectionor transmission temporal profiles along each of multiple beams formed bythe array) for a high resolution image (e.g., with a range from about0.1 to about 2.0 millimeters (mm) of organic tissue at depths into thetissue from about 2 to about 6 cm in each of multiple cross sections(also called slices), e.g., by pointing or sliding or with a 2-D array.Transducer frequencies of 1 to 10 MHz provide an axial resolution fromabout 0.15 mm to about 1.50 mm. In images, this ranges from about 50dots per inch (dpi) and above (corresponding to 20 pixels/cm and above).Above about 600 dpi, disadvantages include increase sensor noise andincreased demands for storage of data. In experimental embodiments, theairway is at least 3 cm deep. It is advantageous to achieve a depth ofpenetration of about 5 cm to include the anterior spine. A transducerfrequency of about 7 MHz and below is advantageous for providing optimalresolution at the deepest tissues in the region of interest (ROI).

In step 1203, a sensor set 222 is provided, and is configured to measuresecond data (e.g., blood oxygen saturation, chest movement, breathingsound, among others, or some combination) sensitive to obstructive sleepapnea (OSA) events in a subject.

In step 1205, communication channels 230 are provided between a computersystem 240 and both the ultrasound transceiver array 212 and the sensorset 222, either directly or indirectly through command modules 214, 224,respectively.

In step 1207, the computer system 240, including any terminal providedwith the transducer array 212, is configured, either by software orspecial purpose circuitry or some combination, to perform severalfunctions. Those functions include one or more of operating the array toobtain one or more images during normal breathing; detect an OSA eventbased on second data communicated from the sensor set; in response todetecting the OSA event, cause the ultrasound transceiver array tocollect data during the event; and present ultrasound images thatindicate location of obstruction in one or more of the multiple crosssections, including storing one or more such images.

In step 1211, the ultrasound transceiver array 212 is placed adjacent toa subject 290 in a position to produce images corresponding to crosssections (slices) of a subject airway from retropalatal to mid trachealanatomical domains. For example, the ultrasound imaging device 210 (alsocalled an ultrasound probe) is removably attached to the subject with anattachment structure 216 that keeps the array 212 near to, or in contactwith, the skin of the subject 290. In some embodiments, step 1211includes operating the transducer array to collect first data for one ormore images that represent corresponding cross-sections in one or moreanatomical domains during normal breathing or normal (non OSA event)sleep. In embodiments to monitor an obstruction previously located, theultrasound transducer array is configured to take successive slicesthrough the location of the obstruction at multiple different times.

In step 1213, the sensor set 222 in placed in position to detect an OSAevent in the subject 290. For example, a pulse oximeter is placed on afinger of the subject, and a microphone is placed on the head of thesubject. In some embodiments, one or more sensors is configured toautomatically alarm, which alarm can be used as a triggering event. Forexample, some telemetric pulse oximetry probes automatically send analarm when oxygen saturation falls below a set threshold, such as 90%SpO₂. In some embodiments to monitor an obstruction previously located,step 1213 is omitted.

In step 1215, the computer system 240 is operated to present one or moreimages that indicate a location of an obstruction in the subject,including storing one or more images as image data 252, based on thefirst data. In some embodiments, the computer system 240 alsoautomatically indicates one or more images, or one or more sub-images(portions of the images), where an obstruction is likely to beindicated. In embodiments to monitor an obstruction previously located,step 1215 includes presenting at each of multiple times, the currentCPAP pressure and a measure at the corresponding time of the air-tissueinterface strength, such as a number of bright pixels in a mask thatmarks the air-tissue interface (e.g., the bright pixels in the posterior40% of FIG. 6L), or the average intensity of pixels from the originalimage inside the mask, both described above, or some other statistic.

In step 1217, the subject is treated based on the location of anobstruction in an image of the one or more images presented or stored instep 1217. For example, if no obstruction is indicated, the subject istreated for a syndrome other than OSA. If an obstruction is identifiedand located, then a CPAP titration pressure is determined based on theCPAP pressure that both opens the airway and is considered tolerable bythe subject. This step is described in more detail below with referenceto FIG. 13. If CPAP is not sufficient, then, in some embodiments,treatment includes a surgical procedure is performed on the subject,e.g., to biopsy or remove a foreign object, if any, or to introduce anobject or remove tissue to prevent obstruction at that location byindigenous tissues. In some embodiments, the location of the obstructionis not automatically determined by the computer system; and, a humananalyst uses the images presented by the computer system in step 1215,and the human analyst determines the location of an obstruction, if any.

In step 1219, it is determined whether there is another subject toexamine. If not, then the method ends. Otherwise, control passes back tostep 1211 to place the transducer array on the next subject, and performthe following steps.

FIG. 13 is a flowchart that illustrates an example method 1300 toperform one or more steps of FIG. 12 to determine CPAP titrationpressure, according to an embodiment. Thus, method 1300 is an exampleembodiment of steps 1215 and 1217 of the method 1200 of FIG. 12 if it isdetermined that airway obstruction is leading to sleep apnea in thesubject.

In step 1301, the CPAP device is operated to increase positive drivingpressure (Pd) in the airway of the subject, e.g., initially from zeropositive pressure (above atmospheric pressure of about 1030 cm of water)to an initial incremental pressure ΔP₀. In general, the new drivingpressure at step n+1 is equal to the current driving pressure at step nplus the increment determined for step n

Pd _(n+1)=Pd _(n)+ΔP _(n)

Where Pd₀=0. ΔP₀ is determined based on the degree of closing observedin the ultrasound images (e.g., the number of bright pixels in the mask,or the average intensity within the mask, both described above, or someother statistic, e.g., mentioned in Wolf et al., 2015) and some estimateof the rate of ultrasound image change per change in pressure. At first,there may be no knowledge of how this individual subject responds to achange in pressure. In such circumstances a guess or historical valuefor ΔP₀ may be used. For example, suppose the historical experienceacross many subjects give a curve as presented in FIG. 10. Because thereis a current obstruction at the starting conditions (n=0), it ispresumed that the air-tissue interface statistic is low (e.g., meanpixel intensity is low, say 10 gray level units). In this example, thepressure to get to the threshold gray level of 150 units depicted inFIG. 10 is read off the chart, say at 300 cm of water. So in this caseΔP₀ is 300 cm of water.

In step 1303 the pixel intensity or count or other statistic in theregion of the airway is monitored under the increased pressure. Forexample, suppose after the increase of pressure, the mean pixelintensity in the mask is 120.

In step 1305 the pixel intensity or count or other statistic change withpressure is determined to establish the actual responsiveness of thecurrent subject to a CPAP pressure change. For example the change of 110grey level units with a change of 300 cm of water give a rate of changeof 0.37 grey level units per cm of water. This actual rate is used in asubsequent execution of step 1301.

In step 1311, it is determined whether the mean pixel intensity orbright pixel count in the mask or other statistic of the strength of theair-tissue interface in the region of the airway is at or above thethreshold amount for that statistic. If not, the airway is considerednot sufficiently open and control passes back to step 1301 to change theCPAP driving pressure Pd again. This time, in step 1301, the ΔP_(n) willbe based on the difference between the current statistic of the strengthof the air-tissue interface and the threshold amount as well as the mostrecent rate of change of the statistic with pressure determined in step1305. For example, the difference between the threshold mean intensityof grey level 150 units and the actual statistic value 120 gray levelunits is 30 gray level units. Using the most recent rate of change of0.37 from step 1305, ΔP₁ is 30/0.37=81 cm H2O, so the new drivingpressure, Pd₁=381 cm H2O. The steps of 1301, 1303, 1305 and 1311 form aloop that is iterated until the statistic is found in step 1311 toexceed or equal the threshold, each time updating the rate of change ofthe statistic of the strength of the air-tissue interface with pressure.In some embodiments the rate of change of the statistic value withpressure is assumed a constant and averaged for subsequent use. In themethod described, the rate is allowed to change at different levels ofairway patency.

If it is determined in step 1311 the mean pixel intensity or brightpixel count in the mask or other statistic of the strength of theair-tissue interface in the region of the airway is at or above thethreshold amount for that statistic, then control passes to step 1313.In step 1313, the CPAP titration pressure is set to the currentpressure. For example, if a pressure of 381 cm H2O does cause the greylevel to exceed 150 units, then in step 1313, the titrated CPAP drivingpressure is set to 381 cm H2O. Though the threshold is reached at thispressure, it is not known whether the current subject will reduce theoccurrences of sleep apnea events at this threshold, which waspredetermined based on other subjects. The following steps are used todetermine whether a change in threshold value for the statistic ofstrength of the air-tissue interface is warranted for the currentsubject.

In step 1321, it is determined whether the pressure is sufficient forthe current subject. For example, the subject is maintained at thispressure for several hours over one or more sleeping sessions; and, thenumber of sleep apnea events is determined, e.g., based on data from thesensing device 220 or from monitoring of the ultrasound slice throughthe known obstruction. The pressure is sufficient if the number ofevents is low enough to satisfy clinical targets, e.g. X events or lessin eight hours, where X is chosen in a range from about 1 to bout 5.Currently X=5 events per eight hours is considered clinical cure in theadult population. If not, then the threshold should be increased, andcontrol passes to step 1323.

In step 1323 the threshold is increased. Any method may be used todetermine the new threshold. For example, based on historical data thatCPAP titration pressures vary among individuals with a mean pressure anda standard deviation that is a fraction of the mean pressure, the changein threshold for the strength of the air-tissue interface could be setbased on that fraction, e.g., the threshold could be increased by 25% ofthat fraction of the original threshold for the strength of theair-tissue interface, or set to the fraction of the pressure changetimes the most recent rate of change of the statistic per change inpressure, or some combination. In some embodiments, adjustments are madeif subject would report sleepiness. It is also possible to measure theinhalation and exhalation volume. For example, if airflow duringrespiration (patient is exhaling) continues to be below what isconsidered mean for the population (referred to as tidal volume), thenthe insufflation pressures are not correct. These are two methods usedto titrate CPAP pressures and can be used in conjunction withultrasonographic estimation to improve accuracy of the system. Controlthen passes back to step 1301 to increase the CPAP driving pressurebased on the new threshold.

If it is determined in step 1321 that the titration pressure issufficient for the current subject, then control passes to step 1331 todetermine whether the titration pressure ought to be reduced. Thisdecision is based on the comfort level of the subject and the amount bywhich the statistic of strength of the air-tissue interface meets orexceeds the current threshold. If the subject is comfortable with thetitration pressure, then the process ends. If the current subjectindicates that the current titration pressure is uncomfortable orinterferes with sleep, then it is determined whether the titrationpressure is reducible. For example, it is determined whether theclinical results exceed the target clinical result or the threshold wasexceeded in step 1311. If the titration pressure is not reducible, thenthe titration pressure is not reduced; and the process ends. However ifthe subject is uncomfortable and the pressure is reducible, then controlpasses to step 1333 to reduce the titration pressure for the currentsubject.

In step 1333 the titration pressure is reduced. Any method may be usedto reduce the pressure. In some embodiments, the pressure is reduced bythe amount the statistic of strength of the air-tissue interface exceedsthe threshold divided by the most recent rate for the change of thestatistic with pressure determined in step 1305 or a historical valuefor the rate based on many prior subjects. In some embodiments, thepressure is reduced by an amount based on an amount by which the timebetween sleep apnea events exceeds the clinical target for that time. Inthis embodiment, if the time is exceeded, then the pressure can bereduced by a small decrement, say a small multiple of the pressureresolution of the CPAP device. In some embodiments, the pressure isreduced using a standardized scale to determine if there is clinicalbenefit. These standardized scales are already in use to screen forsleep apnea, such as the Epworth sleepiness scale. The advantages ofthis approach include ease of use, inexpensive, rapid. A disadvantage ofthis approach is lack of objectivity. IN some embodiments, the pressureis reduced based on calibration achieved using concurrentpolysomnography (sleep study). Currently, it is possible to do a sleepstudy while the patient is being fitted with a CPAP machine to assessresponse to therapy. An advantage of this approach is gold standard ofobjective assessment. Disadvantages include involving a concurrent sleepstudy which entails admission to a facility, many hours of time and highexpense. Control then passes back to step 1313 and following step, toreset the CPAP titration pressure to the lower pressure and determinewhether the new reduced pressure is still sufficient.

3. Computational Hardware Overview

FIG. 14 is a block diagram that illustrates a computer system 1400 uponwhich an embodiment of the invention may be implemented. Computer system1400 includes a communication mechanism such as a bus 1410 for passinginformation between other internal and external components of thecomputer system 1400. Information is represented as physical signals ofa measurable phenomenon, typically electric voltages, but including, inother embodiments, such phenomena as magnetic, electromagnetic,pressure, chemical, molecular atomic and quantum interactions. Forexample, north and south magnetic fields, or a zero and non-zeroelectric voltage, represent two states (0, 1) of a binary digit (bit).).Other phenomena can represent digits of a higher base. A superpositionof multiple simultaneous quantum states before measurement represents aquantum bit (qubit). A sequence of one or more digits constitutesdigital data that is used to represent a number or code for a character.In some embodiments, information called analog data is represented by anear continuum of measurable values within a particular range. Computersystem 1400, or a portion thereof, constitutes a means for performingone or more steps of one or more methods described herein.

A sequence of binary digits constitutes digital data that is used torepresent a number or code for a character. A bus 1410 includes manyparallel conductors of information so that information is transferredquickly among devices coupled to the bus 1410. One or more processors1402 for processing information are coupled with the bus 1410. Aprocessor 1402 performs a set of operations on information. The set ofoperations include bringing information in from the bus 1410 and placinginformation on the bus 1410. The set of operations also typicallyinclude comparing two or more units of information, shifting positionsof units of information, and combining two or more units of information,such as by addition or multiplication. A sequence of operations to beexecuted by the processor 1402 constitutes computer instructions.

Computer system 1400 also includes a memory 1404 coupled to bus 1410.The memory 1404, such as a random access memory (RAM) or other dynamicstorage device, stores information including computer instructions.Dynamic memory allows information stored therein to be changed by thecomputer system 1400. RAM allows a unit of information stored at alocation called a memory address to be stored and retrievedindependently of information at neighboring addresses. The memory 1404is also used by the processor 1402 to store temporary values duringexecution of computer instructions. The computer system 1400 alsoincludes a read only memory (ROM) 1406 or other static storage devicecoupled to the bus 1410 for storing static information, includinginstructions, that is not changed by the computer system 1400. Alsocoupled to bus 1410 is a non-volatile (persistent) storage device 1408,such as a magnetic disk or optical disk, for storing information,including instructions, that persists even when the computer system 1400is turned off or otherwise loses power.

Information, including instructions, is provided to the bus 1410 for useby the processor from an external input device 1412, such as a keyboardcontaining alphanumeric keys operated by a human user, or a sensor. Asensor detects conditions in its vicinity and transforms thosedetections into signals compatible with the signals used to representinformation in computer system 1400. Other external devices coupled tobus 1410, used primarily for interacting with humans, include a displaydevice 1414, such as a cathode ray tube (CRT) or a liquid crystaldisplay (LCD), for presenting images, and a pointing device 1416, suchas a mouse or a trackball or cursor direction keys, for controlling aposition of a small cursor image presented on the display 1414 andissuing commands associated with graphical elements presented on thedisplay 1414.

In the illustrated embodiment, special purpose hardware, such as anapplication specific integrated circuit (IC) 1420, is coupled to bus1410. The special purpose hardware is configured to perform operationsnot performed by processor 1402 quickly enough for special purposes.Examples of application specific ICs include graphics accelerator cardsfor generating images for display 1414, cryptographic boards forencrypting and decrypting messages sent over a network, speechrecognition, and interfaces to special external devices, such as roboticarms and medical scanning equipment that repeatedly perform some complexsequence of operations that are more efficiently implemented inhardware.

Computer system 1400 also includes one or more instances of acommunications interface 1470 coupled to bus 1410. Communicationinterface 1470 provides a two-way communication coupling to a variety ofexternal devices that operate with their own processors, such asprinters, scanners and external disks. In general the coupling is with anetwork link 1478 that is connected to a local network 1480 to which avariety of external devices with their own processors are connected. Forexample, communication interface 1470 may be a parallel port or a serialport or a universal serial bus (USB) port on a personal computer. Insome embodiments, communications interface 1470 is an integratedservices digital network (ISDN) card or a digital subscriber line (DSL)card or a telephone modem that provides an information communicationconnection to a corresponding type of telephone line. In someembodiments, a communication interface 1470 is a cable modem thatconverts signals on bus 1410 into signals for a communication connectionover a coaxial cable or into optical signals for a communicationconnection over a fiber optic cable. As another example, communicationsinterface 1470 may be a local area network (LAN) card to provide a datacommunication connection to a compatible LAN, such as Ethernet. Wirelesslinks may also be implemented. Carrier waves, such as acoustic waves andelectromagnetic waves, including radio, optical and infrared wavestravel through space without wires or cables. Signals include man-madevariations in amplitude, frequency, phase, polarization or otherphysical properties of carrier waves. For wireless links, thecommunications interface 1470 sends and receives electrical, acoustic orelectromagnetic signals, including infrared and optical signals, thatcarry information streams, such as digital data.

The term computer-readable medium is used herein to refer to any mediumthat participates in providing information to processor 1402, includinginstructions for execution. Such a medium may take many forms,including, but not limited to, non-volatile media, volatile media andtransmission media. Non-volatile media include, for example, optical ormagnetic disks, such as storage device 1408. Volatile media include, forexample, dynamic memory 1404. Transmission media include, for example,coaxial cables, copper wire, fiber optic cables, and waves that travelthrough space without wires or cables, such as acoustic waves andelectromagnetic waves, including radio, optical and infrared waves. Theterm computer-readable storage medium is used herein to refer to anymedium that participates in providing information to processor 1402,except for transmission media.

Common forms of computer-readable media include, for example, a floppydisk, a flexible disk, a hard disk, a magnetic tape, or any othermagnetic medium, a compact disk ROM (CD-ROM), a digital video disk (DVD)or any other optical medium, punch cards, paper tape, or any otherphysical medium with patterns of holes, a RAM, a programmable ROM(PROM), an erasable PROM (EPROM), a FLASH-EPROM, or any other memorychip or cartridge, a carrier wave, or any other medium from which acomputer can read. The term non-transitory computer-readable storagemedium is used herein to refer to any medium that participates inproviding information to processor 1402, except for carrier waves andother signals.

Logic encoded in one or more tangible media includes one or both ofprocessor instructions on a computer-readable storage media and specialpurpose hardware, such as ASIC 1420.

Network link 1478 typically provides information communication throughone or more networks to other devices that use or process theinformation. For example, network link 1478 may provide a connectionthrough local network 1480 to a host computer 1482 or to equipment 1484operated by an Internet Service Provider (ISP). ISP equipment 1484 inturn provides data communication services through the public, world-widepacket-switching communication network of networks now commonly referredto as the Internet 1490. A computer called a server 1492 connected tothe Internet provides a service in response to information received overthe Internet. For example, server 1492 provides information representingvideo data for presentation at display 1414.

The invention is related to the use of computer system 1400 forimplementing the techniques described herein. According to oneembodiment of the invention, those techniques are performed by computersystem 1400 in response to processor 1402 executing one or moresequences of one or more instructions contained in memory 1404. Suchinstructions, also called software and program code, may be read intomemory 1404 from another computer-readable medium such as storage device1408. Execution of the sequences of instructions contained in memory1404 causes processor 1402 to perform the method steps described herein.In alternative embodiments, hardware, such as application specificintegrated circuit 1420, may be used in place of or in combination withsoftware to implement the invention. Thus, embodiments of the inventionare not limited to any specific combination of hardware and software.

The signals transmitted over network link 1478 and other networksthrough communications interface 1470, carry information to and fromcomputer system 1400. Computer system 1400 can send and receiveinformation, including program code, through the networks 1480, 1490among others, through network link 1478 and communications interface1470. In an example using the Internet 1490, a server 1492 transmitsprogram code for a particular application, requested by a message sentfrom computer 1400, through Internet 1490, ISP equipment 1484, localnetwork 1480 and communications interface 1470. The received code may beexecuted by processor 1402 as it is received, or may be stored instorage device 1408 or other non-volatile storage for later execution,or both. In this manner, computer system 1400 may obtain applicationprogram code in the form of a signal on a carrier wave.

Various forms of computer readable media may be involved in carrying oneor more sequence of instructions or data or both to processor 1402 forexecution. For example, instructions and data may initially be carriedon a magnetic disk of a remote computer such as host 1482. The remotecomputer loads the instructions and data into its dynamic memory andsends the instructions and data over a telephone line using a modem. Amodem local to the computer system 1400 receives the instructions anddata on a telephone line and uses an infra-red transmitter to convertthe instructions and data to a signal on an infra-red a carrier waveserving as the network link 1478. An infrared detector serving ascommunications interface 1470 receives the instructions and data carriedin the infrared signal and places information representing theinstructions and data onto bus 1410. Bus 1410 carries the information tomemory 1404 from which processor 1402 retrieves and executes theinstructions using some of the data sent with the instructions. Theinstructions and data received in memory 1404 may optionally be storedon storage device 1408, either before or after execution by theprocessor 1402.

FIG. 15 illustrates a chip set 1500 upon which an embodiment of theinvention may be implemented. Chip set 1500 is programmed to perform oneor more steps of a method described herein and includes, for instance,the processor and memory components described with respect to FIG. 14incorporated in one or more physical packages (e.g., chips). By way ofexample, a physical package includes an arrangement of one or morematerials, components, and/or wires on a structural assembly (e.g., abaseboard) to provide one or more characteristics such as physicalstrength, conservation of size, and/or limitation of electricalinteraction. It is contemplated that in certain embodiments the chip setcan be implemented in a single chip. Chip set 1500, or a portionthereof, constitutes a means for performing one or more steps of amethod described herein.

In one embodiment, the chip set 1500 includes a communication mechanismsuch as a bus 1501 for passing information among the components of thechip set 1500. A processor 1503 has connectivity to the bus 1501 toexecute instructions and process information stored in, for example, amemory 1505. The processor 1503 may include one or more processing coreswith each core configured to perform independently. A multi-coreprocessor enables multiprocessing within a single physical package.Examples of a multi-core processor include two, four, eight, or greaternumbers of processing cores. Alternatively or in addition, the processor1503 may include one or more microprocessors configured in tandem viathe bus 1501 to enable independent execution of instructions,pipelining, and multithreading. The processor 1503 may also beaccompanied with one or more specialized components to perform certainprocessing functions and tasks such as one or more digital signalprocessors (DSP) 1507, or one or more application-specific integratedcircuits (ASIC) 1509. A DSP 1507 typically is configured to processreal-world signals (e.g., sound) in real time independently of theprocessor 1503. Similarly, an ASIC 1509 can be configured to performedspecialized functions not easily performed by a general purposedprocessor. Other specialized components to aid in performing theinventive functions described herein include one or more fieldprogrammable gate arrays (FPGA) (not shown), one or more controllers(not shown), or one or more other special-purpose computer chips.

The processor 1503 and accompanying components have connectivity to thememory 1505 via the bus 1501. The memory 1505 includes both dynamicmemory (e.g., RAM, magnetic disk, writable optical disk, etc.) andstatic memory (e.g., ROM, CD-ROM, etc.) for storing executableinstructions that when executed perform one or more steps of a methoddescribed herein. The memory 1505 also stores the data associated withor generated by the execution of one or more steps of the methodsdescribed herein.

4. Alternatives, Variations and Modifications

In the foregoing specification, the invention has been described withreference to specific embodiments thereof. It will, however, be evidentthat various modifications and changes may be made thereto withoutdeparting from the broader spirit and scope of the invention. Thespecification and drawings are, accordingly, to be regarded in anillustrative rather than a restrictive sense. Throughout thisspecification and the claims, unless the context requires otherwise, theword “comprise” and its variations, such as “comprises” and“comprising,” will be understood to imply the inclusion of a stateditem, element or step or group of items, elements or steps but not theexclusion of any other item, element or step or group of items, elementsor steps. Furthermore, the indefinite article “a” or “an” is meant toindicate one or more of the item, element or step modified by thearticle. As used herein, unless otherwise clear from the context, avalue is “about” another value if it is within a factor of two (twice orhalf) of the other value. While example ranges are given, unlessotherwise clear from the context, any contained ranges are also intendedin various embodiments. Thus a range from 0 to 10 includes the range 1to 4 in some embodiments.

5. References

The contents of each of the following references are hereby incorporatedby reference as if fully set forth herein except for terminology that isinconsistent with that used herein.

Bhattacharyya, N., Blake, S. P. & Fried, M. P. 2000. Assessment of theairway in obstructive sleep apnea syndrome with 3-dimensional airwaycomputed tomography. Otolaryngology-Head and Neck Surgery 123: 444-449.

Chaban, R., Cole, P. & Hoffstein, V. 1988. Site of upper airwayobstruction in subjects with idiopathic obstructive sleep apnea.Laryngoscope 98: 641-647.

Clement, G., White, J. & Hynynen, K. 2000. Investigation of a large-areaphased array for focused ultrasound surgery through the skull. Physicsin Medicine and Biology 45, 1071.

Collop, N., Anderson, W. M., Boehlecke, B., Claman, D., Goldberg, R.,Gottlieb, D. J., Hudgel, D., Sataia, M., & Schwab, R. 2007. Clinicalguidelines for the use of unattended portable monitors in the diagnosisof obstructive sleep apnea in adult subjects. J Clin Sleep Med 3:737-747.

Crane, J. P., LeFevre, M. L., Winborn, R. C., Evans, J. K., Ewigman, B.G., Bain, R. P., Frigoletto, F. D., McNellis, D., & RADIUS Study Group.1994. A randomized trial of prenatal ultrasonographic screening: impacton the detection, management, and outcome of anomalous fetuses. Am JObstetrics and Gynecology 171: 392.

Croft, C. & Pringle, M. 1991. Sleep nasendoscopy: a technique ofassessment in snoring and obstructive sleep apnoea. ClinicalOtolaryngology & Allied Sciences 16: 504-509.

Deberry-Borowiecki, B., Kukwa, A. & Blanks, R. H. 1988. Cephalometricanalysis for diagnosis and treatment of obstructive sleep apnea.Laryngoscope 98: 226-234.

Ezri, T., Gewürtz, G., Sessler, D. I., Medalion, B., Szmuk, P., Hagberg,C., & Susmallian, S. 2003. Prediction of difficult laryngoscopy in obesesubjects by ultrasound quantification of anterior neck soft tissue.Anaesthesia 58: 1111-1114.

Findley, L., Barth J. T., Powers D. C., Wilhoit S. C., Boyd D. G. &Suratt P. M. 1986. Cognitive impairment in subjects with obstructivesleep apnea and associated hypoxemia. Chest 90(5): 686-690.

Flemons, W. W. 2002. Obstructive sleep apnea. New England Journal ofMedicine 347: 498-504.

Gardin, J. M., FASE, M. G.-H., Jaff, M. & Mohler, E. 2006. Clinicalapplication of noninvasive vascular ultrasound in cardiovascular riskstratification: a report from the American Society of Echocardiographyand the Society of Vascular Medicine and Biology. J Am Soc Echocardiogr19: 943-954.

Girard, E. E. 2003. Automated Detection of Obstructive Sleep Apnea UsingUltrasound Imaging. Charlottesville, Va.: University of Virginia.

Guilleminault, C., Connolly, S. J. & Winkle, R. A. 1983. Cardiacarrhythmia and conduction disturbances during sleep in 400 subjects withsleep apnea syndrome. American J Cardio 52: 490-494.

Guilleminault, C., Riley, R. & Powell, N. 1984. Obstructive sleep apneaand abnormal cephalometric measurements. Implications for treatment.Chest 86: 793-794.

Hamers, R., Bruining, N., Knook, M., Sabate, M. & Roelandt, J. 2001. ANovel Approach to Quantitative Analysis of Intra Vascular UltrasoundImages. In: Computers in Cardiology. IEEE: 589-592.

Hoskins, P. R., Martin, K. & Thrush, A. 2010. Diagnostic ultrasound:physics and equipment. Cambridge, U.K.: Cambridge University Press.

Hudgel, D. W. 1986. Variable site of airway narrowing among obstructivesleep apnea subjects. J Applied Physiology 61: 1403-1409.

Hung, J., Whitford, E., Hillman, D. & Parsons, R. Association of sleepapnoea with myocardial infarction in men. 1990. Lancet 336: 261-264.

Johns, M. W. 1993. Daytime sleepiness, snoring, and obstructive sleepapnea: The Epworth Sleepiness Scale. Chest 103(1): 30-36.

Kajekar, P., Mendonca, C. & Gaur, V. 2010. Role of Ultrasound in AirwayAssessment and Management. International J Ultrasound & AppliedTechnologies in Perioperative Care 1: 97-100.

Kuratli, C. & Huang, Q. 2000. A CMOS ultrasound range-findermicrosystem. IEEE Journal of Solid-State Circuits 35: 2005-2017.

Marin, J. M., Carrizo, S. J., Vicente, E. & Agusti, A. G. 2005.Long-term cardiovascular outcomes in men with obstructive sleepapnoea-hypopnoea with or without treatment with continuous positiveairway pressure: an observational study. Lancet 365: 1046-1053.

McNay, M. B. & Fleming, J. E. 1999. Forty years of obstetric ultrasound1957-1997: From A-scope to three dimensions. Ultrasound in Medicine andBiology 25: 3-56.

Morrison, D., Launois, S. H., Isono, S., Feroah, T. R., Whitelaw, W. A.,& Remmers, J. E. 1993. Pharyngeal narrowing and closing pressures insubjects with obstructive sleep apnea. American J Respiratory andCritical Care Medicine 148(3): 606-611.

Muthukumaran, S., Yang, K., Seuren, A., Kentish, S., Ashokkumar, M.,Stevens, G. W., & Grieser, F. 2004. The use of ultrasonic cleaning forultrafiltration membranes in the dairy industry. Separation andpurification technology 39, 99-107.

Pepin, J., Ferretti, G., Veale, D., Romand, P., Coulomb, M., Brambilla,C., & Lévy, P. A. 1992. Somnofluoroscopy, computed tomography, andcephalometry in the assessment of the airway in obstructive sleepapnoea. Thorax 47(3): 150-156.

Riley, R., Guilleminault, C., Powell, N. & Simmons, F. 1985.Palatopharyngoplasty failure, cephalometric roentgenograms, andobstructive sleep apnea. Otolaryngology-Head and Neck Surgery 93: 240.

Riley, R. W., Powell, N. B. & Guilleminault, C. 1993. Obstructive sleepapnea syndrome: a review of 306 consecutively treated surgical subjects.Otolaryngology-Head and Neck Surgery 108: 117.

Rodenstein, D., Dooms, G., Thomas, Y., Liistro, G., Stanescu, D. C.,Culee, C., & Aubert-Tulkens, G. 1990. Pharyngeal shape and dimensions inhealthy subjects, snorers, and subjects with obstructive sleep apnoea.Thorax 45(10): 722-727.

Romero, R. Routine obstetric ultrasound. 2003. Ultrasound in Obstetrics& Gynecology 3: 303-307.

Ruecroft, G., Hipkiss, D., Ly, T., Maxted, N. & Cains, P. W. 2005.Sonocrystallization: the use of ultrasound for improved industrialcrystallization. Organic process research & development 9: 923-932.

Schwab, R. J., Pasirstein, M., Pierson, R., Mackley, A., Hachadoorian,R., Arens, R., Maislin, G., & Pack, A. I. 2003. Identification of upperairway anatomic risk factors for obstructive sleep apnea with volumetricmagnetic resonance imaging. American J Respiratory and Critical CareMedicine 168(5): 522-530.

Shamsuzzaman, A. S., Gersh, B. J. & Somers, V. K. 2003. Obstructivesleep apnea. JAMA: the journal of the American Medical Association 290:1906-1914.

Shelton, K. E., Woodson, H., Gay, S. & Suratt, P. M. 1993. Pharyngealfat in obstructive sleep apnea. American Journal of Respiratory andCritical Care Medicine 148: 462-466.

Shepard, J. W. & Thawley, S. E. 1990. Localization of upper airwaycollapse during sleep in subjects with obstructive sleep apnea. AmericanJournal of Respiratory and Critical Care Medicine 141: 1350-1355.

Siegel, H., Sonies, B. C., Graham, B., McCutchen, C., Hunter, K.,Vega-Bermudez, F., & Sato, S. 2000. Obstructive sleep apnea: A study bysimultaneous polysomnography and ultrasonic imaging. Neurology 54:1872-1872.

Silk, M. G. 1984. Ultrasonic transducers for nondestructive testing.London: Taylor & Francis.

Smith, S., Trahey, G. & Von Ramm, 0. 1986. Phased array ultrasoundimaging through planar tissue layers. Ultrasound in Medicine & Biology12: 229-243.

Strollo Jr, P. J. & Rogers, R. M. 1996. Obstructive sleep apnea. NewEngland Journal of Medicine 334: 99-104.

Teran-Santos, J., Jimenez-Gomez, A. & Cordero-Guevara, J. 1999. Theassociation between sleep apnea and the risk of traffic accidents. NewEngland J Med 340: 847-851.

Veasey, S. C., Guilleminault, C., Strohl, K. P., Sanders, M. H.,Ballard, R. D., & Magalang, U. J. 2006. Medical therapy for obstructivesleep apnea: a review by the Medical Therapy for Obstructive Sleep ApneaTask Force of the Standards of Practice Committee of the AmericanAcademy of Sleep Medicine. Sleep 29(8): 1036.

Wolf, J., & Isaiah, A., 2015, U.S. Patent Application Publication No.US2015/0209001.

1. A method implemented on a processor comprising: automaticallyreceiving a plurality of ultrasound images representing a cross sectionof an airway in a neck of a subject obtained by an ultrasound transducerarray directed toward the subject at a corresponding plurality ofdifferent times; automatically receiving a plurality of differentpositive pressure values imposed by a device on the airway of thesubject at the corresponding plurality of different times; for each ofthe plurality of ultrasound images, automatically forming a mask ofpixels associated with an air-tissue interface; for each of theplurality of ultrasound images, automatically determining a value of astatistic of pixels within the mask; automatically determining atitration pressure for a continuous positive airway pressure (CPAP)device based on the plurality of positive pressures and the value of thestatistic for each of the plurality of ultrasound images; and presentingon an display device output data that indicates the titration pressurefor the CPAP device.
 2. A method as recited in claim 1, whereindetermining the titration pressure comprises determining the titrationpressure based on one or more pressures of the plurality of differentpositive pressures which occur at one or more times of the correspondingplurality of different times when the value of the statistic of pixelswithin the mask is above a threshold value.
 3. A method as recited inclaim 1, wherein presenting on a display device output data thatindicates the titration pressure for the CPAP device further comprisesoperating the CPAP device at the titration pressure.
 4. A method asrecited in claim 1, wherein the statistic is mean intensity value withinthe mask.
 5. A method as recited in claim 1, wherein the statistic is anumber of pixels within the mask.
 6. A method as recited in claim 1,wherein the statistic is a number of pixels having an intensity above aminimum intensity within the mask.
 7. A method as recited in claim 2,further comprising determining the threshold value based on operating aCPAP machine at one or more positive pressure values of the plurality ofdifferent positive pressure values until a clinical target is achieved.8. A method as recited in claim 1, further comprising after, determiningthe titration pressure, reducing the titration pressure if the titrationpressure before reduction interferes with sleep of the subject.
 9. Acomputer-readable medium carrying one or more sequences of instructions,wherein execution of the one or more sequences of instructions by one ormore processors causes the one or more processors to perform the stepsof: automatically receiving a plurality of ultrasound imagesrepresenting a cross section of an airway in a neck of a subjectobtained by an ultrasound transducer array directed toward the subjectat a corresponding plurality of different times; automatically receivinga plurality of different positive pressure values imposed by a device onthe airway of the subject at each of the corresponding plurality ofdifferent times; for each of the plurality of ultrasound images,automatically forming a mask of pixels associated with an air-tissueinterface; for each of the plurality of ultrasound images, automaticallydetermining a value of a statistic of pixels within the mask;automatically determining a titration pressure for a continuous positiveairway pressure (CPAP) device based on the plurality of positivepressures and the value of the statistic for each of the plurality ofultrasound images; and presenting on an display device output data thatindicates the titration pressure for the CPAP device.
 10. A systemcomprising: an ultrasound transducer array configured to be disposedadjacent to a neck of a subject; a continuous positive airway pressure(CPAP) device; at least one processor; and at least onecomputer-readable medium including one or more sequences ofinstructions, the at least one computer-readable medium and the one ormore sequences of instructions configured to, with the at least oneprocessor, cause the system to perform at least the following,automatically receiving a plurality of ultrasound images representing across section of an airway in a neck of the subject obtained by theultrasound transducer array directed toward the subject at acorresponding plurality of different times; automatically receiving aplurality of different positive pressure values imposed by the CPAPdevice on the airway of the subject at the corresponding plurality ofdifferent times; for each of the plurality of ultrasound images,automatically forming a mask of pixels associated with an air-tissueinterface; for each of the plurality of ultrasound images, automaticallydetermining a value of a statistic of pixels within the mask;automatically determining a titration pressure for the CPAP device basedon the plurality of positive pressures and the value of the statisticfor each of the plurality of ultrasound images; and operating the CPAPdevice at the titration pressure.
 11. A method implemented on aprocessor comprising: automatically receiving a first plurality ofultrasound images representing a cross sections of an airway in a neckof a subject obtained by an ultrasound transducer array directed towardthe subject at a corresponding plurality of different times; determininga region of interest comprising a subset of pixels of each image of thefirst plurality of ultrasound images, wherein each region of interestencompasses an airway of the subject; for each of the plurality ofimages, automatically forming a mask of pixels associated with anair-tissue interface based on both a morphological opening and amorphological closing with a structural element in the region ofinterest if the mask includes at least a minimum number of pixels; foreach of the plurality of images, automatically determining a value of astatistic of pixels within the mask; presenting on an display deviceoutput data that indicates a degree of airway patency proportional tothe value of the statistic at each of the corresponding plurality ofdifferent times.
 12. A method as recited in claim 11, wherein thestatistic is mean intensity value within the mask.
 13. A method asrecited in claim 11, wherein the statistic is a number of pixels withinthe mask.
 14. A method as recited in claim 11, wherein the statistic isa number of pixels having an intensity above a minimum intensity withinthe mask.
 15. A method as recited in claim 11, wherein the minimumnumber of pixels is
 20. 16. A method as recited in claim 11, wherein thestructural element is diamond shaped.
 17. A computer-readable mediumcarrying one or more sequences of instructions, wherein execution of theone or more sequences of instructions by one or more processors causesthe one or more processors to perform the steps of: automaticallyreceiving a first plurality of ultrasound images representing a crosssections of an airway in a neck of a subject obtained by an ultrasoundtransducer array directed toward the subject at a correspondingplurality of different times; determining a region of interestcomprising a subset of pixels of each image of the first plurality ofultrasound images, wherein each region of interest encompasses an airwayof the subject; for each of the plurality of images, automaticallyforming a mask of pixels associated with an air-tissue interface basedon both a morphological opening and a morphological closing with astructural element in the region of interest if the mask at least aminimum number of pixels; for each of the plurality of images,automatically determining a value of a statistic of pixels within themask; presenting on an display device output data that indicates adegree of airway patency proportional to the value of the statistic ateach of the corresponding plurality of different times.
 18. A systemcomprising: at least one processor; and at least one computer-readablemedium including one or more sequences of instructions, the at least onecomputer-readable medium and the one or more sequences of instructionsconfigured to, with the at least one processor, cause the system toperform at least the following, automatically receiving a firstplurality of ultrasound images representing a cross sections of anairway in a neck of a subject obtained by an ultrasound transducer arraydirected toward the subject at a corresponding plurality of differenttimes; determining a region of interest comprising a subset of pixels ofeach image of the first plurality of ultrasound images, wherein eachregion of interest encompasses an airway of the subject; for each of theplurality of images, automatically forming a mask of pixels associatedwith an air-tissue interface based on both a morphological opening and amorphological closing with a structural element in the region ofinterest if the mask at least a minimum number of pixels; for each ofthe plurality of images, automatically determining a value of astatistic of pixels within the mask; presenting on an display deviceoutput data that indicates a degree of airway patency proportional tothe value of the statistic at each of the corresponding plurality ofdifferent times.